Apnoea of Prematurity (AOP): Definition

• Defined as cessation of breathing in excess of 15

seconds duration, typically accompanied by
desaturation and bradycardia.

– Desaturation – Decrease in oxygen saturation

– Bradycardia – Decrease in heart rate

Paediatric Respiratory Reviews (2004) 5(Suppl a), s377–s382

 Types of apnoea

3 Types
• Central apnoea: is characterized by total cessation of
inspiratory efforts with no evidence of obstruction.
• Obstructed apnoea: In obstructed apnoea, the infant tries
to breathe against an obstructed upper airway resulting in
chest wall motion without airflow throughout the entire
apnoea.
• Mixed apnoea: Consists of obstructed respiratory efforts
usually following central pauses, and is probably the most
common type of apnoea.

Mixed apnoea typically accounts

accounts for
for more than
than half of all
all long
apnoeic episodes, followed in decreasing frequency by central and
obstructive apnoea.
apnoea.

Paediatric Respiratory Reviews (2004) 5(Suppl a), s377–s382

 Prevalence

• Incidence of AOP is inversely proportional to

gestational age.
• Varies from 10 % in infants born at 34 weeks of
gestation to > 60 % in infants born at < 28 weeks
of gestation.
• Usually presents after 1-2 days of life and within
first 7 days.
• pathological apnoea of prematurity often ceases
altogether by the time the infant reaches a
postconceptional age of 37 weeks
Every 3 out
out of 5 babies
babies born
born at GA
GA << 28
28 weeks
weeks develop
develop AOP

Indian J Pediatr 2008; 75 ( 1) : 57 -61

 Pathophysiology

There are 2 aspects

• Cessation of breathing
• Response to cessation of breathing

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Physiology of control of breathing

Basic function of Respiratory control system is to:

Maintain normal partial pressure of oxygen(PO2), partial
pressure of carbon dioxide (PCO2) and hydrogen ion
concentration (pH) in the face of large changes in
oxygen (O2) consumption and carbon dioxide (CO2)
production.

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Physiology of control of breathing

This complex control involves:

• Central brainstem processing: Respiratory
centre in brainstem
• Central and peripheral chemo receptors
• Irritant and mechanoreceptors
• Endogeneous neuroregulators: Inhibit or
stimulate respiration

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Central Brainstem control

• The brainstem controls the

periodicity of respiration
• Receives afferent input
from upper airways, the
lungs and the peripheral
and central
chemoreceptors,

Best Practice and Research Anaesthesiology 2010; 24: 323-336

Peripheral and central chemo receptors

• Peripheral chemo
receptors in the
carotid body contain
specialized cells that
detect oxygen
• The chemo receptors
are sensitive to CO2,
pH, glucose,
osmolality and
temperature changes

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Endogenous neuroregulators

• Adenosine, gamma-aminobutyric acid (GABA),

serotonin, endorphins and prostaglandin.
• Inhibit or stimulate respiration
• Adnosine inhibits respiration

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Laryngeal chemorefex

• The laryngeal mucosa is sensitive to chemical or

mechanical stimulation, which will cause a strong
inhibitory reflex – the laryngeal chemoreflex.

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Stretch receptors in the lung

• Cause reflex negative feedback to respiration.

• The Herring–Breuer inflation-stretch reflex results in a
decrease in respiratory drive whilst the deflation
reflex leads to an increased respiratory rate.

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 The change from foetus to neonate

Foetal refexes:
• Foetal respiratory efforts result in no change in
arterial O2 and CO2;
• The foetus will become apnoeic when hypoxic, which
confers some advantage by decreasing oxygen
consumption

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Foetal response

• The foetal response to hypoxia is decrease in

respiratory effort
• Response to hypercapnia is an increase in
breathing depth, but not frequency

These foetal reflexes change over the first few

weeks of life to become more like the normal
adult reflex

Best Practice and Research Anaesthesiology 2010; 24: 323-336

 Normal Adult Reflex

Cessation of Breathing

Inreased blood CO2

Decreased oxygen saturation Hypoxia
Hypercapnea

J Arab Neonatal Forum 2005; 2 : 63-73

 Neonatal Reflex

Cessation of Breathing

Inreased blood CO2

Decreased oxygen saturation Hypoxia
Hypercapnea

J Arab Neonatal Forum 2005; 2 : 63-73

 AOP in preterm neonates

Apnoea of prematurity is thought to be

secondary to immaturity of brainstem
centers that regulate breathing

J Arab Neonatal Forum 2005; 2 : 63-73

 Preterm Neonates

Immaturity of
respiratory control
system

Exaggerated Altered Hypoxic

inhibitory response to depression
reflexes hypercapnea

Apnoea

J Arab Neonatal Forum 2005; 2 : 63-73

Altered response to hypercapnea

Response to hypercapnea

Preterm Neonates Term Neonates or Adults

Impaired Response,
Increase in both
Increase in TV but no
TV & RR
increase in RR

Breathing response to CO22 in preterm infants and

especially those with apnoea is impaired when
compared to term neonates or adults.

J Arab Neonatal Forum 2005; 2 : 63-73

 Hypoxic ventilatory depression

• Once hypoxia occurs it would appear to aggravate

apnoea and result in delayed recovery of the infant.
• Probable causes:
– Decrease in PaCO2 secondary to the initial
hyperventilation
– hypoxia-mediated central depression of ventilation
– Multiple neurotransmitters have been implicated as
mediators for hypoxic depression including
adenosine,endorphins and GABA
• Hypoxic ventilatory depression is more pronounced
in preterm babies

J Arab Neonatal Forum 2005; 2 : 63-73

 Exaggerated inhibitory reflexes

• Exaggerated laryngeal reflex-induced apnoea

• Stimulation of pulmonary stretch receptors through
increasing lung volume causes apnoea
• This reflex, known as the Hering-Breuer reflex
• In preterm infants the Hering-Breuer reflex is
more active
• The purpose of such an exaggerated reflex is
probably to prevent both over distention and full
emptying of the lung, so maintaining lung volume at
end expiration.

J Arab Neonatal Forum 2005; 2 : 63-73

 Other causes

• Decrease in diaphragm activity is

common to both central and mixed
apnoea
• Delayed upper airway muscle activation
may prolong the episode.

Paediatric Respiratory Reviews 2004; 5(Suppl a): s377–s382

 Apnoea of prematurity

Cessation of breathing
incr. vagal tone

decr. O2 delivery

Bradycardia Desaturation

Carotid body

J Arab Neonatal Forum 2005; 2 : 63-73

Paediatric Rspiratory Reviews (2004) 5(Suppl A), s377–s382
 Secondary Causes

• Temperature Instability: Hypothermia & hyperthermia

• Neurobiological : Birth trauma, drugs, IVH, seizures,
congenital myopathies, neuropathies
• Pulmonary: RDS, Pneumonia, Pulmonary
haemorrhage, pneumothorax,
• Position of head & neck: Neck flexion
• Cardiac: Congenital cynotic heart disease,
hypotension / hypertension, congestive heart failure,
patent ductus arteriosus

Indian J Pediatr 2008; 75 (1) : 57 -61

 Secondary Causes

• Gastrointestinal: Gastro esophageal reflux,

abdominal distension
• Infection: Sepsis, pneumonia, meningitis,
necrotizing enterocolitis
• Metabolic : Acidosis , hypoglycemia,
hyponatremia, hypernatremia, inborn errors of
metabolism

Indian J Pediatr 2008; 75 (1) : 57 -61

 Consequences

Immediate Consequences
• Hypoxia, hypercarbia, bradycardia and changes in blood pressure.
Delayed Consequences
• Morbidity and mortality
• Irreversible neurological damage
• Blindness from bilateral retrolental fibroplasia
• Sensorineural deafness
However it is unclear if severe squeale relate to
• Retardation
apnoea alone and linking recurrent apnoeas with
• Spastic diplegia or quadriplegia
poorer neurodevelopmental outcome is difficult.
• Although infants born before 32 weeks gestation have a three-
times- higher risk of sudden infant death syndrome (SIDS), there
appears to be no link with history of apnoeas in these infants.

Clin Pediatr 2000; 39: 327 -336,

Best Practice & Research Clinical Anaesthesiology 2010; 24 : 324 323–336
 Diagnosis

• Diagnosis is by exclusion and other secondary

causes should be ruled out.
• All babies< 34 weeks of gestation should be
monitored for at least first week of life or till absence
of apnoeic episodes for at least 1 week.

Onset of apnea within first 7 days in a premature

infant (GA < 34 weeks) would be suggestive of AOP.

Indian J Pediatr 2008; 75 (1) : 57 -61

 Diagnosis

Pulse Oxymeter: Detect changes in heart rate and

oxygen saturation

Indian J Pediatr 2008; 75 (1) : 57 -61

 Other Apnoea monitors

• Movement sensors: They

interpret chest / abdominal
movements as respiration
• Limitation: Fail to diagnose
obstructive apnoea
• May not distinguish body
movements from apnoea

Indian J Pediatr 2008; 75 (1) : 57 -61

 Other Apnea monitors

• Thoracic impedence based

monitors: They translate changes
in thoracic impedence that occur
with breathing as respiratory
activity
• Limitation: Fail to diagnose
obstructive apnoea

Indian J Pediatr 2008; 75 ( 1) : 57 -61

 Other Apnea monitors

• Respiratory inductive plethysmography: Uses

abdominal and thoracic movements during
respiration.
• Magnetometer: Electrical signals produced by chest
and abdominal movement that can be detected by
the sensor.
• Limitation: Fail to diagnose obstructive apnoea

Indian J Pediatr 2008; 75 (1) : 57 -61

 Further Evaluation

R/O secondary causes

• History: Pertaining to perinatal asphyxia,
maternal drugs etc
• Clinical Examination: Hypotension,
jaundice, pallor, temperature instability,
cardiac murmur

Indian J Pediatr 2008; 75 (1) : 57 -61

 Further Evaluation

Investigations – To r/o secondary causes

Blood tests:
• Blood glucose
• Hematocrit
• Electrolytes
• Sepsis screen
• Blood culture
• Arterial blood gas
Radiological tests:
• Chest X-ray, Abdominal X-ray, Ultrasound head etc
Other Investigations may be asked for depending on
the history and physical examination

Indian J Pediatr 2008; 75 (1) : 57 -61

 Treatment

General Measures
• Neck should be positioned with slight extension
• Tactile stimulation
• Oxygen by head box or nasal canula
• If does not respond to tactile stimulation, ventilation
with bag and mask using 100% oxygen
• If this fails, mechanical ventilation

Indian J Pediatr 2008; 75 (1) : 57 -61

 Treatment

Pharmacotherapy
• Methylxanthines: Methylxanthines have been the
mainstay of pharmacologic treatment of apnea.
• They act by inhibiting adenosine receptors that
leads to:
– Increase minute ventilation,
– Improve CO2 sensitivity,
– Decrease hypoxic depression of breathing,
– Enhance diaphragmatic activity, and
– Decrease periodic breathing

Indian J Pediatr 2008; 75 (1) : 57 -61

 Pharmacotherapy

Methylxanthines used are:

• Theophylline: The recommended loading dose of
theophylline is 5-7 mg/kg, followed by maintenance doses
of 5-7 mg/kg/day divided into two or three doses given
orally.
• Aminophylline: It is approximately 80% theophylline. It is
given as a loading dose of 5-7 mg/kg IV, and maintenance
dose 1.5-2.0 mg/kg/dose every 6-8 hours IV
• Caffeine citrate: Given as a loading dose of 20 mg/kg IV,
and maintenance dose of 5 mg/kg IV or orally

Indian J Pediatr 2008; 75 (1) : 57 -61

 Pharmacotherapy

Doxapram
• Doxapram is a potent respiratory stimulant
• But possible effects usually not sustained after
48 hours
• Associated with serious side effects
• To be used only if neonates fail to respond to
methylxanthine therapy or CPAP

Indian J Pediatr 2008; 75 (1) : 57 -61

 Treatment Options

CPAP –
• Administered using nasal prongs/nasopharyngeal
tube
• Used if apnoeic episodes persist despite
optimum methylxanthine therapy
• CPAP of 5 cm of H20 used
• Decreases obstructive and mixed apnoea

Indian J Pediatr 2008; 75 (1) : 57 -61

 Methylxanthines for AOP

AOP was first recognized in the late 1960s

and early 1970s.
1960 and early 1970
At that time, the only remedy for AOP was
the use of mechanical ventilation and
supplemental oxygen

The first trial using aminophylline in the

1973 premature babies was completed in the
United Kingdom and published in 1973.

Neonatal Network 2011; 30:408-12

 Methylxanthines for AOP

Throughout the next two to three decades,

additional studies summarized in a 2001
Cochrane Review confirmed the benefits of
1973-2000
methylxanthines, including theophylline and
caffeine for the treatment of apnoea in the
premature.

Neonatal Network 2011; 30:408-12

Limitations of Aminophylline/Theophylline

• Narrow therapeutic index

• Need for monitoring of plasma concentration

• Dosing frequency 2-3 times daily

• Side effects like tachycardia and GI intolerance

There was a need for a drug with better safety

and ease of administration
 MethylXanthines for AOP

Commercially available preparations

of both injectable and oral Cafcit®
1900-2000
received U.S. FD A approval in 1999
and 2000, respectively

Neonatal Network 2011; 30:408-12

Since it’s approval caffeine citrate is a
methylxanthine of choice for AOP

• Proven efficacy in AOP

• Wider therapeutic index

• Less adverse effects
• Long half-life and once daily dosing

Neonatal Network 2011; 30:408-12

 Composition

• Caffeine citrate Injection & Oral Solution

• Each ml. contains:
Caffeine citrate …20mg
(Equivalent to 10 mg of caffeine IP)
 Mechanism of action

Antagonism of adenosine receptors, both

A1 and A2 subtypes
• Stimulation of the respiratory center,
• Increased minute ventilation
• Decreased threshold to hypercapnia
• Increased response to hypercapnia,
• Increased skeletal muscle tone
• Decreased diaphragmatic fatigue
 Pharmacokinetics

Cmax 6-10 mg/L

Tmax 30 minutes to 2 hours
Distribution Rapidly distributed into the brain
(mean volume of distribution of caffeine in infants 0.8-0.9 L/kg)
Metabolism Hepatic cytochrome P450 1A2 (CYP1A2)
Interconversion between caffeine and theophylline has been
reported in preterm neonates.
Elimination In neonates, the T1/2 is approximately 3-4 days
.By 9 months of age, the metabolism of caffeine approximates that
seen in adults (T1/2 = 5 hours)

Orally administered caffeine citrate is rapidly and completely

absorbed; the pharmacokinetics of caffeine are largely
independent of the route of administration
 Indication

• Caffeine citrate is indicated for the short term

treatment of apnoea of prematurity in infants
between 28 and 33 weeks gestational age. 
 Caffeine citrate :
Efficacy & Safety Study
 Aim

• To evaluate the efficacy and safety of caffeine citrate

for treatment of apnoea of prematurity.

Pharmacotherapy 2000;20(6):644–652)
 Study Design

• This is a multicenter, randomized, double-blind,

placebo-controlled trial with open-label rescue
which included 85 infants, born at gestational age
of 28–32 weeks
• They were included in study ≥ 24 hours after birth
and if they had six or more apnoea episodes
within 24 hours.

Pharmacotherapy 2000;20(6):644–652)
 Study Design

• They were randomized to receive

– Caffeine citrate (n=45) or
– Placebo (n=37), for up to 10 days.
• Infants failing double-blind therapy could receive
Open-Label rescue

Pharmacotherapy 2000;20(6):644–652)
 Dosing Regimen

• A loading dose of caffeine citrate solution 10 mg/kg

as caffeine base (1 ml/kg) or equal volume of placebo
was administered intravenously over 30 minutes with
a syringe infusion pump.
• Approximately 24 hours after the loading dose, a
daily maintenance dose of caffeine citrate 2.5 mg/kg
as caffeine base (0.25 ml/kg) or equal volume of
placebo was administered intravenously over 10
minutes or orally through an orogastric or nasogastric
tube, followed by a single rinse of physiologic saline
through the tube.
 Assessment parameters

• Occurrence of apnoea episodes

• Plasma concentrations of caffeine citrate in
premature infants receiving the agent for up to 12
days.
• Adverse effects

• Apnoea was defined as cessation of breathing for an interval

greater than 20 seconds.
• Success was defined as at least a 50% reduction in apnoea
episodes from baseline events and elimination of apnoea.

Pharmacotherapy 2000;20(6):644–652)
Results
Significantly greater number of infants had reduction in the number
of apnoea episodes by at least 50% of baseline as compared to
placebo from day 3 onwards

80 *
68.9
70
60
50
43
% infants

40
30
20
10
0
Placebo Caffeine citrate

* p=0.02

Pharmacotherapy 2000;20(6):644–652)
 Significantly greater number of infants had elimination of
apnoea episodes as compared to placebo from day 2 onwards

30

25 24.4

20
% infants

15

10

0
0
Placebo Caffeine citrate

Pharmacotherapy 2000;20(6):644–652)
 Plasma concentration

• Plasma concentrations of caffeine citrate were

consistent during the study and remained within
8–20 μg/ml.
• None were greater than 50 μg/ml, the level
reported to be associated with serious toxicity

Pharmacotherapy 2000;20(6):644–652)
 Safety Results

• No clinically significant differences were seen in

number and percentage of adverse events between
groups
• Four infants receiving caffeine citrate and two
receiving placebo experienced necrotizing
enterocolitis (NEC).
• The disorder was determined to be possibly related
to caffeine citrate in one infant and unrelated in the
three others.

Pharmacotherapy 2000;20(6):644–652)
 Safety Results

Percentages of Most Frequently Reported Adverse Events

Treatment Group
Adverse event Caffeine Citrate Placebo
Injection site reaction 8.7 12.8
Perinatal disorder (trace 8.7 5.1
aspirates, feeding intolerance)
Constipation 17.4 20.5
Gastrointestinal disorder 4.3 7.7
(gastroesophageal reflux,
dilated loops of bowel)
Anemia 6.5 17.9
Hyponatremia 0 5.1
Rash 8.7 7.7

Pharmacotherapy 2000;20(6):644–652)
 Conclusion

• Caffeine citrate is safe and effective for treating

apnoea of prematurity in infants born at gestational
age between 28–32 weeks

Pharmacotherapy 2000;20(6):644–652)
 Caffeine vs. Theophylline

• Randomized controlled trial

• Included 44 babies with GA < 31 weeks with AOP
• Divided into 3 groups
– Group A: Standard dose Caffeine (Loading dose 25
mg/kg caffeine citrate and maintenance dose of
6mg/kg orally)
– Group B: High dose caffeine citrate (Loading dose 50
mg/kg caffeine citrate and maintenance dose of 12
mg/kg orally)
– Group C: Theophylline (Loading dose 7.5 mg/kg orally
followed by maintenance dose 3 mg/kg three times
daily)

Arch Dis Childhood 1992;67:425 -428

 Assessment Parameters

• Response to treatment
– Successful treatment if reduction in no of apnoeic
episodes > 50 %
• Plasma concentration
• Side effects

Arch Dis Childhood 1992;67:425 -428

 Response to treatment

• Significant reduction in apnoeic episodes

within 24 hrs
• Successful treatment response was observed
in all infants from all 3 groups except one
infant (retrospectively found to have
secondary cause) at the end of 48 hrs

Similar Efficacy

Arch Dis Childhood 1992;67:425 -428

 Plasma concentration

80
73
69
70
Plasma concentration in the
% infants with desirable plasma

60 56 desired range (13-20 mg/l for

concentration of drug

50 group A, 36-40 mg/l for group B,

13-20 mg/l for group C) was
40 observed in more no of infants in
caffeine groups than theophylline
30 group
20

10

0
GroupA Group B Group C

Predictable plasma concentration

Arch Dis Childhood 1992;67:425 -428

 Adverse Effects

• Plasma concentration of theophylline > 20 mg/l was

associated with persistent tachycardia ( HR > 195)
• 5 out of 12 infants in theophylline group needed
dose adjustment or omission due to persistent
tachycardia but in caffeine group, only 1 from group
A and none from group B needed dose adjustment
 Mean increase in heart rate

14 **
Mean increase in heart rate ( Beats / minute)

12
12
*p< 0.05
** p < 0.01
10

8 Significantly greater increase in

heart rate in theophylline group
6 5 compared to both caffeine groups
was observed on the fourth day of
4 3 treatment.

0
GroupA Group B Group C

Less risk of side effects (tachycardia) with caffeine

 Conclusion

• Use of caffeine is recommended for treatment of

neonatal apnoea as once daily dosing allows easy
administration and plasma concentration attained is
more predictable.

Arch Dis Childhood 1992;67:425 -428

 Caffeine vs. Theophylline

Caffeine Theophylline/Aminophylline
Route of Oral /IV Oral /IV
administration
Onset of toxicity Plasma conc > 50 mg/L May occur at plasma level of
13mg/L
Therapeutic range 5-25 mg/L 5-13 mg/L
Loading dose 10 mg/kg caffeine base 5-7 mg/kg
Maintenance dose 2.5 mg/kg once daily 2 mg/kg 8-12 hrly
Side effects Less, Comparable to More
placebo Tachycardia
GI intolerance
Excitability
Monitoring plasma Infrequently Frequently
concentrations

Paediatr Drugs 2001; 3 (1): 61-79

Caffeine citrate as second line therapy

AOP unresponsive to
theophylline
 Study Design

• Two small, noncomparative, nonblind trials have

shown oral caffeine to be effective in treating apnoea
in premature neonates following failure of
theophylline to do so
• All neonates had persistent clinical apnoea despite
receiving theophylline for at least 7 days (theophylline
plasma concentrations ranged from8 to 12mg/Lin 1
study and were described as adequate in the other

Paediatr Drugs 2001; 3 (1): 61-79

 Summary of the studies

Study 1 Study2
No. of treated 11 16
BW (g) 1660 1600
GA (wk) 31.2 32.7
PNA (d) 20.3 26.2
Dose (PO)
Loading C 10 mg/kg CC 20 mg/kg
Maintenance C 2.5 mg/kg/day CC 5-7.5 mg/kg/day

Paediatr Drugs 2001; 3 (1): 61-79

 Results

Study 1 Study 2
9 pts (82%) had a significant reduction 14 pts (88%) had a successful
in apnoeic episodes. response;
The apnoea density
Frequency of apnoea lasting >20 sec decreased to 0.8 in the
reduced from a mean of 10.1 before to caffeine citrate success Group
1.2 episodes (88% reduction) of (Apnoea density is defined by total
apnoea per 6 hour recording (p < 0.05) apnoea time × 100 divided by
after administration of Caffeine citrate recording time)
An apnoea density of <3, with no
observed bradycardia
associated with shorter apnoeic
events, was considered
a successful response to CC
treatment.

Paediatr Drugs 2001; 3 (1): 61-79

 Concerns with methylxanthines

• Uncertainty about long-term efficacy & safety

• The potential for harm exists because:
– Methylxanthines are inhibitors of adenosine
receptors.
– Adenosine preserves brain ATP levels and
protects brain cells during experimental hypoxia
and ischemia in a variety of animal models.
– Methylxanthines also increase oxygen
consumption in preterm infants and may therefore
diminish growth.

N Engl J Med 2006;354:2112-21.

 Long-term Efficacy &
Safety Study of Caffeine for apnoea of
prematurity (CAP) Trial

N Engl J Med 2006;354:2112-21.

 Study Design

• Large international randomized trial included 2006

infants with birth weight of 500 to 1250 g with apnoea
during the first 10 days of life and randomized to receive
either caffeine or placebo, until drug therapy for apnea of
prematurity was no longer needed.
• They received an intravenous loading dose of either 20
mg of caffeine citrate /kg body weight or an equivalent
volume of normal saline. This was followed by a daily
maintenance dose of 5 mg/kg
Results: Short-term outcomes before home
discharge
Caffeine significantly reduced the frequency of
bronchopulmonary dysplasia

50 46.9
45
40
*
36.3
% Neonates with BPD

35
30
25
20
15
10
5
0
Placebo Caffeine citrate

* P < 0.001
 Other Results

• Positive airway pressure was discontinued one week

earlier in the infants assigned to caffeine (median
postmenstrual age, 31.0 weeks;) than in the infants in
the placebo group (median postmenstrual age, 32.0
weeks; P<0.001).
• The rates of death, ultrasonographic signs of brain
injury, and necrotizing enterocolitis did not differ
significantly between the two groups.
 Conclusion

• Caffeine therapy for apnoea of prematurity reduces the

rate of bronchopulmonary dysplasia in infants with very
low birth weight.
• The recognition that bronchopulmonary dysplasia is an
important risk factor for neurosensory impairment in
early childhood suggests the potential for long-term
benefits of caffeine therapy
• Caffeine has no apparent short-term risks
Long-term Outcomes

N Engl J Med 2007;357:1893-1902.

 Primary Outcomes Assessed

• Death before a corrected age of 18 months or

survival with one or more of the following
– Cerebral palsy
– Cognitive delay
– Hearing loss
– Bilateral blindness

N Engl J Med 2007;357:1893-1902

 Cerebral Palsy

• Cerebral palsy was diagnosed if the child had a

nonprogressive motor impairment characterized by
abnormal muscle tone and decreased range or control
of movements
• The level of gross motor function was determined with
the use of the Gross Motor Function Classification
• A normal level of 0 is assigned if the child is able to
walk 10 steps independently at 18 months. Levels
between 3 and 5 (the highest possible score) indicate
progressively more serious limitations of gross motor
function.
 Cognitive delay

• Cognitive delay was defined as a Mental Development

Index score of less than 85 (1 SD below the mean of
100) on the Bayley Scales of Infant Development
• The score was assumed to be less than 85 if the child
could not be tested because of severe developmental
delay.
 Caffeine significantly improved the rate of survival without
neurodevelopmental disability at a corrected age of 18 to 21 months.

47 46.2
46
% infants who died or survived with

* P = 0.008
neurodevlopmental disability

45
44
43
42
*
41 40.2
40
39
38
37
Placebo Caffeine citrate
Treatment with caffeine as compared with placebo reduced
the incidence of cerebral palsy & cognitive delay

45
Placebo
40 Caffeine citrate 38.3
*
35 33.8

30
% incidence

25
*P = 0.04
* *P =20
0.009

15
10 **
7.3
4.4
5
0
Cerebral palsy Cognitive delay
 Other Results

• The rates of death, deafness, and blindness did not

differ significantly between the two groups.
 Conclusion

• Caffeine therapy for apnoea of prematurity improves

the rate of survival without neurodevelopmental
disability at 18 to 21 months in infants with very low
birth weight.
 Directions for Use

Prior to Administration
• Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea
should be ruled out or properly treated prior to initiation of caffeine citrate
• Prior to initiation of caffeine citrate injection or oral solution, baseline serum
levels of caffeine should be measured in infants previously treated with
theophylline, since preterm infants metabolize theophylline to caffeine.
Likewise, baseline serum levels of caffeine should be measured in infants
born to mothers who consumed caffeine prior to delivery, since caffeine
readily crosses the placenta.
• Caffeine citrate injection/oral solution should be inspected visually for
particulate matter and discoloration prior to administration. Vials containing
discolored solution or visible particulate matter should be discarded
• It is important that the dose of caffeine citrate injection or oral solution be
measured accurately, i.e., with a 1cc or other appropriate syringe.
 Dosage & Administration

The recommended loading dose and maintenance doses of caffeine citrate are as follows.

Dose of Caffeine Dose of Route Frequency

Citrate Volume Caffeine
Citrate mg/kg
Loading 1 mL/kg 20 mg/kg Intravenous* One Time
Dose (over 30
minutes)
Maintenance 0.25 mL/kg 5 mg/kg Intravenous* Every 24
Dose (over 10 hours**
minutes) or
Caffeine
Citrate oral
solution, Orally
* using a syringe infusion pump
** beginning 24 hours after the loading dose
 Administration

• NOTE THAT THE DOSE OF CAFFEINE BASE IS

ONE-HALF THE DOSE WHEN EXPRESSED AS
CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is
equivalent to 10 mg of caffeine base).
• Each vial is for single use only. Any unused portion of
the medication should be discarded.
 After administration

• Reports in the published literature have raised a

question regarding the possible association between
the use of methylxanthines and development of
necrotizing enterocolitis, although a causal relationship
between methylxanthine use and necrotizing
enterocolitis has not been established.
• Therefore, as with all preterm infants, patients being
treated with caffeine citrate should be carefully
monitored for the development of necrotizing
enterocolitis
 After administration

• Serum concentrations of caffeine may need to be

monitored periodically throughout treatment to
avoid toxicity Serious toxicity has been associated
with serum levels greater than 50 mg/L. 
• In clinical studies reported in the literature, cases
of hypoglycemiaand hyperglycemia have been
observed. Therefore, serum glucose may need to
be periodically monitored in infants receiving
caffeine citrate.
 Use in Special Populations

• Infants with cardiovascular disease

Although no cases of cardiac toxicity were reported in the
placebo-controlled trial, caffeine has been shown to increase
heart rate, left ventricular output, and stroke volume in
published studies. Therefore, caffeine citrate should be used
with caution in infants with cardiovascular disease
• Infants with seizure disorders
Caffeine is a central nervous system stimulant and in cases of
caffeine overdose, seizures have been reported. Caffeine
citrate should be used with caution in infants with seizure
disorders
 
 Use in Special Populations

Renal / hepatic Impairment

• Caffeine citrate should be administered with caution
in infants with impaired renal function or impaired
hepatic function.
• Serum concentrations of caffeine should be
monitored and dose administration of caffeine citrate
should be adjusted to avoid toxicity in this population 
 Drug interactions

• Few data exist on drug interactions with caffeine in

preterm neonates.
• Based on adult data, lower doses of caffeine may be
needed following co administration of drugs which are
reported to decrease caffeine elimination (e.g., cimetidine
and ketoconazole) and higher caffeine doses may be
needed following co administration of drugs that increase
caffeine elimination (e.g., phenobarbital and phenytoin).
• Interconversion between caffeine and theophylline has
been reported in preterm neonates. The concurrent use of
these drugs is not recommended
 Contraindications

• Caffeine citrate is contraindicated in patients who have

demonstrated hypersensitivity to any of its
components.
 Overdosage

• Serious toxicity has been associated with serum levels

greater than 50 mg/L.
• Signs and symptoms reported in the literature after
caffeine overdose in preterm infants include fever,
tachypnea, jitteriness, insomnia, fine tremor of the
extremities, hypertonia vomiting, hyperglycemia etc.
• Seizures have also been reported in cases of overdose.  
• Treatment of caffeine overdose is primarily symptomatic
and supportive. Caffeine levels have been shown to
decrease after exchange transfusions. Convulsions may
be treated with intravenous administration of diazepam or
a barbiturate such as pentobarbital sodium.
 Undesirable Effects

• Overall, the reported number of adverse events in the

double-blind period of the controlled trial was similar for
the caffeine citrate and placebo group
• Published long-term follow-up studies have not shown
caffeine to adversely affect neurological development or
growth parameters.
 Other Uses

• Prophylactic therapy for AOP: Evidence inconclusive

• In periextubation period
– Methylxanthines are used to facilitate weaning and extubation of
ventilated neonates, especially in very low birth weight infants
– Methylxanthines are usually given 24 hours prior to a planned
extubation.
– European consensus guidelines on management of neonatal
RDS -2010 update recommend –
• Caffeine should be used in babies with apnoea and to facilitate
weaning from MV (A).
• Caffeine should be considered for all babies at high risk of
needing ventilation, such as those < 1,250 g birth weight and
who are managed on CPAP or NIPPV (B).

Arch Dis Child Fetal Neonatal Ed. 2004;89(6):F499-503, Neonatology 2010;97:402–417

 Other Uses

Postoperative apnoea
• Preterm infants who undergo general anesthesia for
surgery may have episodes of apnoea, cyanosis and
bradycardia during the early postoperative period.
• Caffeine given at the time of surgery may be able to
prevent post-operative apnoea and bradycardia in
preterm babies.

International Health 2009;1: 190-195

Few Hurdles in acceptance of caffeine citrate

• Cost
• Vial is for single time use so wastage of drug
 How to overcome these hurdles ?

• After opening vial, drug can be used for 2-3 babies

with AOP in NICU.
• Can select a preparation with small vial size ( e.g.
1ml /2ml)
 To Conclude
• Caffeine citrate is considered as a first-line treatment for apnoea of prematurity and
should be preferred to theophylline/aminophylline as
• Proven efficacy in reducing the frequency of apnoeic attacks and use of mechanical
ventilation in preterm infants
• Similar efficacy to theophylline or aminophylline and better tolerability profile with
less adverse effects like tachycardia/feed intolerance
• Effective in treating apnoea in premature neonates unresponsive to theophylline
• More predictable plasma concentration than theophylline
• No need for routine measurements of blood concentrations unlike theophylline
• Has wider therapeutic index hence more safe to use
• Longer half life allows once daily dosing whereas theophylline or aminophylline needs
to be given 2-3 times daily.
• US FDA approved drug
• Reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight.
• Improves the rate of survival without neurodevelopmental disability at 18 to 21
months in infants with very low birth weight.
Caffeine citrate for AOP
Thank You